Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia

NCT04447989 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: Pro001049011R61HL147833-01
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 25

Brief Summary

This is a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study of sildenafil in premature infants (inpatient in Neonatal Intensive Care Units (NICUs)) with severe bronchopulmonary dysplasia (BPD).

Conditions

Bronchopulmonary Dysplasia of Newborn

Outcome Measures

Primary Outcomes (1)

• Safety Based Upon Number of Participants With Hypotension

  Safety as determined by incidence of hypotension experienced by the participants through 28 days post last dose of study drug. Hypotension will be defined as any clinically significant low blood pressure event deemed by the treating physician to require intervention with a fluid bolus or the initiation or escalation of inotropic, vasopressor, or systemic steroid therapy with the specific intent to raise blood pressure.

  28 days post last dose of study drug, up to 9 weeks

Secondary Outcomes (5)

• Central Volume of Distribution (Vc) Population Pharmacokinetics (popPK)

  Following the completion of 7 days (168 hours) of study drug administration

• Peripheral Volume of Distribution (Vp) Population Pharmacokinetics (popPK)

  Following the completion of 7 days (168 hours) of study drug administration

• Clearance Population Pharmacokinetics (popPK)

  Following the completion of 7 days (168 hours) of study drug administration

• Half-life Population Pharmacokinetics (popPK)

  Following the completion of 7 days (168 hours) of study drug administration

• Peak Plasma Concentration Population Pharmacokinetics (popPK)

  Following the completion of 7 days (168 hours) of study drug administration

Other Outcomes (1)

• Number of Participants at Each Global Rank

  28 days post last dose of study drug, up to 9 weeks

Study Arms (6)

Cohort 1, sildenafil

ACTIVE COMPARATOR

Sildenafil (0.5 mg/kg IV or 1 mg/kg enteral) every 8 hours for 28 days

Drug: Sildenafil

Cohort 1, placebo

PLACEBO COMPARATOR

Placebo (IV or enteral) every 8 hours for 28 days

Drug: Placebo

Cohort 2, sildenafil

ACTIVE COMPARATOR

Sildenafil (1 mg/kg IV or 2 mg/kg enteral) every 8 hours for 28 days

Drug: Sildenafil

Cohort 2, placebo

PLACEBO COMPARATOR

Placebo (IV or enteral) every 8 hours for 28 days

Drug: Placebo

Cohort 3, sildenafil

ACTIVE COMPARATOR

Sildenafil (2 mg/kg IV or 4 mg/kg enteral) every 8 hours for 28 days

Drug: Sildenafil

Cohort 3, placebo

PLACEBO COMPARATOR

Placebo (IV or enteral) every 8 hours for 28 days

Drug: Placebo

Interventions

Sildenafil DRUG

Sildenafil citrate injection or powder for suspension

Also known as: Revatio

Cohort 1, sildenafil; Cohort 2, sildenafil; Cohort 3, sildenafil

Placebo DRUG

dextrose 5%

Also known as: Dextrose 5%

Cohort 1, placebo; Cohort 2, placebo; Cohort 3, placebo

Eligibility Criteria

• Age: Up to 29 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Documented informed consent from parent or guardian, prior to study procedures
• \< 29 weeks gestational age at birth
• weeks postmenstrual age
• Receiving respiratory support at enrollment:
• If 32 0/7-35 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional)
• If 36 0/7-44 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional) OR continuous positive airway pressure (CPAP)
• Note:
• Criteria 3 and 4 define severe BPD for the purposes of this study
• CPAP is defined as any of the following:
• Nasal cannula \> 2 liters per minute (LPM)
• Nasal continuous positive airway pressure (NCPAP)
• Nasal intermittent positive pressure ventilation (NIPPV)
• Noninvasive neurally adjusted ventilatory assist (NAVA)
• Any other device designed to provide positive pressure through a nasal device (e.g., RAM cannula, etc.)

You may not qualify if:

• Previous enrollment and dosing in this study, protocol number (NHLBI-2019-SIL), "Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia (BPD)"
• Previous exposure to sildenafil within 7 days prior to randomization\*
• Previous exposure to vasopressors within 24 hours prior to randomization\*
• Previous exposure to inhaled nitric oxide within 24 hours prior to randomization\*
• Previous exposure to milrinone within 24 hours prior to randomization\*
• Evidence of pulmonary hypertension or moderate/large patent ductus arteriosus (PDA) on the most recent echocardiogram performed within 14 days prior to randomization
• Known major congenital heart defect requiring medical or surgical intervention in the neonatal period
• Known allergy to sildenafil
• Known sickle cell disease
• Aspartate aminotransferase (AST) \> 225 U/L \< 72 hours prior to randomization
• Alanine aminotransferase (ALT) \> 150 U/L \< 72 hours prior to randomization
• Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study.
• Participant will be reassessed prior to dosing to reconfirm eligibility criteria.

Sponsors & Collaborators

• Christoph Hornik: lead
• University of North Carolina, Chapel Hill: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (25)

Arkansas Children's Research Institute

Little Rock, Arkansas, 72202, United States

Location

University of Arkansas Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

Rady Children's Hospital and Health Center

San Diego, California, 92123, United States

Location

Childrens National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

University of Florida Jacksonville Shands Medical Center

Jacksonville, Florida, 32209, United States

Location

Wolfson Children's Hospital

Jacksonville, Florida, 32209, United States

Location

Emory Children's Center

Atlanta, Georgia, 30322, United States

Location

Lurie Children's Hospital

Chicago, Illinois, 60611-2605, United States

Location

University of Illinois at Chicago

Chicago, Illinois, 60611, United States

Location

University of Kentucky Chandler Medical Center

Lexington, Kentucky, 40506, United States

Location

University of Louisville School of Medicine

Louisville, Kentucky, 40202, United States

Location

Ochsner Baptist Medical Center

New Orleans, Louisiana, 70115, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Childrens Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Children's Hospital of Nevada at University Medical Center

Las Vegas, Nevada, 89102, United States

Location

University of Rochester School of Medicine Children's Hospital

Rochester, New York, 14642, United States

Location

Westchester Medical Center - New York Medical College

Valhalla, New York, 10595, United States

Location

University of NC at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

East Carolina University

Greenville, North Carolina, 27858, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Rainbow Babies and Childrens Hospital

Cleveland, Ohio, 44106, United States

Location

University of Tennessee Health Science Center

Memphis, Tennessee, 38163, United States

Location

University of Texas Health

Austin, Texas, 78723, United States

Location

Women's Hospital of Texas

Houston, Texas, 77054, United States

Location

Related Publications (11)

• Gonzalez D, Laughon MM, Smith PB, Ge S, Ambalavanan N, Atz A, Sokol GM, Hornik CD, Stewart D, Mundakel G, Poindexter BB, Gaedigk R, Mills M, Cohen-Wolkowiez M, Martz K, Hornik CP; Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee. Population pharmacokinetics of sildenafil in extremely premature infants. Br J Clin Pharmacol. 2019 Dec;85(12):2824-2837. doi: 10.1111/bcp.14111. Epub 2019 Dec 15.

  PMID: 31475367 BACKGROUND

• Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, Laptook AR, Sanchez PJ, Van Meurs KP, Wyckoff M, Das A, Hale EC, Ball MB, Newman NS, Schibler K, Poindexter BB, Kennedy KA, Cotten CM, Watterberg KL, D'Angio CT, DeMauro SB, Truog WE, Devaskar U, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015 Sep 8;314(10):1039-51. doi: 10.1001/jama.2015.10244.

  PMID: 26348753 BACKGROUND

• Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001 Jun;163(7):1723-9. doi: 10.1164/ajrccm.163.7.2011060. No abstract available.

  PMID: 11401896 BACKGROUND

• Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007 Dec;120(6):1260-9. doi: 10.1542/peds.2007-0971.

  PMID: 18055675 BACKGROUND

• Morrow CB, McGrath-Morrow SA, Collaco JM. Predictors of length of stay for initial hospitalization in infants with bronchopulmonary dysplasia. J Perinatol. 2018 Sep;38(9):1258-1265. doi: 10.1038/s41372-018-0142-7. Epub 2018 Jun 8.

  PMID: 29880793 BACKGROUND

• Jackson W, Hornik CP, Messina JA, Guglielmo K, Watwe A, Delancy G, Valdez A, MacArthur T, Peter-Wohl S, Smith PB, Tolia VN, Laughon MM. In-hospital outcomes of premature infants with severe bronchopulmonary dysplasia. J Perinatol. 2017 Jul;37(7):853-856. doi: 10.1038/jp.2017.49. Epub 2017 Apr 6.

  PMID: 28383537 BACKGROUND

• Poets CF, Lorenz L. Prevention of bronchopulmonary dysplasia in extremely low gestational age neonates: current evidence. Arch Dis Child Fetal Neonatal Ed. 2018 May;103(3):F285-F291. doi: 10.1136/archdischild-2017-314264. Epub 2018 Jan 23.

  PMID: 29363502 BACKGROUND

• Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999 Jun 24;340(25):1962-8. doi: 10.1056/NEJM199906243402505.

  PMID: 10379020 BACKGROUND

• Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065.

  PMID: 16707748 BACKGROUND

• Doyle LW, Ehrenkranz RA, Halliday HL. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2014 May 13;(5):CD001146. doi: 10.1002/14651858.CD001146.pub4.

  PMID: 24825456 BACKGROUND

• Schneider S, Bailey M, Spears T, Esther CR Jr, Laughon MM, Hornik CP, Jackson W. Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study. BMC Pediatr. 2020 Dec 14;20(1):559. doi: 10.1186/s12887-020-02453-7.

  PMID: 33317479 DERIVED

MeSH Terms

Conditions

Bronchopulmonary Dysplasia

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Christoph Hornik, MD, PhD, MPH
• Organization: Duke University

christoph.hornik@duke.edu

919-668-4000

Study Officials

• Christoph Hornik, MD

  Duke UMC

  PRINCIPAL INVESTIGATOR

• Matt Laughon, MD

  UNC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Study drug (sildenafil or placebo) will be prepared in the pharmacy by the unblinded pharmacist. Treatment cohort will be randomly assigned electronically and communicated to the pharmacist via the study portal. All other study staff and the patients/parents will be blinded to the treatment assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Model Details: Premature infants with severe BPD (inpatient in neonatal intensive care units) will be randomized in a dose escalating approach 3:1 (sildenafil: placebo) sequentially, into each of 3 cohorts. There will be approximately 40 randomized and dosed participants in each cohort for a total of up to 120 participants.

Study Record Dates

• First Submitted: June 22, 2020
• First Posted: June 25, 2020
• Study Start: May 27, 2021
• Primary Completion: December 12, 2024
• Study Completion: January 15, 2025
• Last Updated: January 26, 2026
• Results First Posted: January 26, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (25)